Long-term assessment of clinical outcomes and disease progression in patients with corrected Tetralogy of Fallot.

OBJECTIVE: Understanding changes of right ventricular (RV) geometry and function in repaired Tetralogy of Fallot (rToF) patients can improve decision-making for pulmonary valve replacement. Therefore, we aimed to assess the magnitude and clinical correlations of RV changes in rToF patients. PATIENTS AND METHODS: Clinical and MRI data of rToF patients who underwent repeated cardiac magnetic resonance imaging (MRI) at two centers between December 2003 and September 2020 were analyzed together with anatomical factors, including RV outflow tract obstruction, pulmonary artery branch stenosis, and tricuspid regurgitation. Adverse cardiac events and/or NYHA class worsening were documented and correlated with MRI changes. QRS length was reported at each MRI. RESULTS: Two-hundred-and-nineteen rToF patients (53% males, aged 20.2 ± 10.1 years) were enrolled. An increase of ventricular dimensions, except LVEDVi, and worsening of right and left ejection fractions were found over an average period of 5 years of follow-up. These changes were statistically significant but within 10% of the initial value. No significant changes were reported on a year-to-year basis, except in a small group of patients (6%) in whom no predictive factors were identified. Despite similar RV dimensions at the first examination, younger patients had a higher RV ejection fraction and a different annual rate of change of ventricular dimensions compared to older ones. Patients with arrhythmias (20%) were more frequently older and had larger RV dimensions but showed no significant correlations with MRI changes/years. CONCLUSIONS:  Changes in RV dimensions and function occur rarely and very slowly in rToF patients. A small percentage of patients experience a significant worsening in a short time interval without any recognized risk factors. Arrhythmias appear to occur in a small percentage of cases in the late follow-up.

Successful muscle regeneration by a homologous microperforated scaffold seeded with autologous mesenchymal stromal cells in a porcine esophageal substitution model.

BACKGROUND: Since the esophagus has no redundancy, congenital and acquired esophageal diseases often require esophageal substitution, with complicated surgery and intestinal or gastric transposition. Peri-and-post-operative complications are frequent, with major problems related to the food transit and reflux. During the last years tissue engineering products became an interesting therapeutic alternative for esophageal replacement, since they could mimic the organ structure and potentially help to restore the native functions and physiology. The use of acellular matrices pre-seeded with cells showed promising results for esophageal replacement approaches, but cell homing and adhesion to the scaffold remain an important issue and were investigated. METHODS: A porcine esophageal substitute constituted of a decellularized scaffold seeded with autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) was developed. In order to improve cell seeding and distribution throughout the scaffolds, they were micro-perforated by Quantum Molecular Resonance (QMR) technology (Telea Electronic Engineering). RESULTS: The treatment created a microporous network and cells were able to colonize both outer and inner layers of the scaffolds. Non seeded (NSS) and BM-MSCs seeded scaffolds (SS) were implanted on the thoracic esophagus of 4 and 8 pigs respectively, substituting only the muscle layer in a mucosal sparing technique. After 3 months from surgery, we observed an esophageal substenosis in 2/4 NSS pigs and in 6/8 SS pigs and a non-practicable stricture in 1/4 NSS pigs and 2/8 SS pigs. All the animals exhibited a normal weight increase, except one case in the SS group. Actin and desmin staining of the post-implant scaffolds evidenced the regeneration of a muscular layer from one anastomosis to another in the SS group but not in the NSS one. CONCLUSIONS: A muscle esophageal substitute starting from a porcine scaffold was developed and it was fully repopulated by BM-MSCs after seeding. The substitute was able to recapitulate in shape and function the original esophageal muscle layer.

Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart malformations, characterized by underdevelopment of the structures in the left heart-aorta complex. The majority of cases are sporadic. Although multiple genetic loci have been tentatively implicated in HLHS, no gene or pathway seems to be specifically associated with the disease. To elucidate the genetic basis of HLHS, we analyzed 53 well-characterized patients with isolated HLHS using an integrated genomic approach that combined DNA sequencing of five candidate genes (NKX2-5, NOTCH1, HAND1, FOXC2 and FOXL1) and genome-wide screening by high-resolution array comparative genomic hybridization. In 30 patients, we identified two novel de novo mutations in NOTCH1, 23 rare patients inherited gene variants in NOTCH1, FOXC2 and FOXL1, and 33 rare patients mostly inherited copy-number variants. Some of the identified variations coexisted in the same patient. The biological significance of such rare variations is unknown, but our findings strengthen the role of NOTCH pathway in cardiac valve development, indicating that HLHS is, at least in part, a 'valve' disease. This is the first report of de novo mutations associated with isolated HLHS. Moreover, the coexistence of multiple rare variants suggests in some cases a cumulative effect, as shown for other complex disease.

C2 and C0 values for monitoring cyclosporine therapy in stable heart transplant recipients.

INTRODUCTION: We sought to evaluate the behavior of C2 values and their correlation with acute rejection episodes and cyclosporine (CyA) side effects in heart transplant patients whose immunosuppressive therapy, was monitored with C0 trough levels. METHODS: Sixty stable patients who had received heart transplants from 3 months to 60 months prior were randomly observed from September 2001 to June 2004. Four area under the concentration-time curves (AUC) were performed on each patient, a total of 240 AUC curves. RESULTS: Regarding the variability of CyA absorption, two groups of patients were distinguished: group A, "constant absorbers," namely, low variability (<15%) of CyA absorption; group B, "inconstant absorbers" patients with higher (>15%) variability of absorption. Group B patients showed more acute rejection episodes (41%) than group A (19%). CyA side effects were more serious in patients with higher variability of absorption: systemic hypertension, neurological disorders, hyperlipidemia, and gum hyperplasia; Group B patients who developed CyA side effects showed higher maximum and mean C2 levels (P < .05) than group A patients. No differences were found with regard to renal dysfunction between the two groups: all patients showed a mean increase of serum creatinine by at least 50% compared to the baseline value. CONCLUSION: Higher C2 levels were not sufficient to predict acute rejection compared to lower but constants, C2 levels. Patients with inconstant absorption were more often overexposed to CyA than underexposed, developing more side effects than patients with lower variability of absorption. Monitoring CyA therapy with C0 and C2 may prevent over- or underexposure to the drug.

Cesarean section using the Misgav Ladach method.

OBJECTIVE: To stress the advantages of the Misgav Ladach method for cesarean section. STUDY DESIGN: In this study operative details and the postoperative course of 139 patients who underwent cesarean section according to the Misgav Ladach method in 1995-96 are presented. RESULTS: The Misgav Ladach method reduces operation time, time of child delivery, and time of recovery. The rates of febrile morbidity, wound infection and wound dehiscence are not affected by the new technique. CONCLUSION: Our study highlights the efficiency and safety of the Misgav Ladach method, and points out the speeded recovery, with early ambulation and resumption of drinking and eating, that makes the cesarean section delivery closer and closer to natural childbirth.

Endometriosis and infertility: our experience over five years.

During a 5-year period, we diagnosed endometriosis by laparoscopy in 163 infertile patients (7.9% of the infertile population). Seventy-one women presented with minimal endometriosis, 32 women a mild form, 38 women a moderate form and 22 women a severe form. Only 40 patients (24.5%) were found to have endometriosis as the only abnormality in a complete fertility work-up. One hundred and twenty patients were treated with Danazol (600 mg daily for 4-6 months) and 33 of them conceived (27.5%). Twenty-eight patients received conservative surgical treatment associated with Danazol therapy and 11 of them conceived (39.2%). In the 15 patients with minimal endometriosis, who had no therapy but expectant management, there were two conceptions within one year (13.3%). The anticipation of minimal disease in patients with endometriosis as the only abnormality produced about the same results as achieved by active treatment (pregnancy rate of 33.3% after expectant management and 36.3% after treatment). These results suggest that minimal endometriosis can be anticipated only when there are no co-existing factors of infertility.